UCHL1 acts as a prognostic factor and promotes cancer stemness in cervical squamous cell carcinoma

Cervical cancer is one of the three major malignant tumors of female reproductive system, and its morbidity and mortality rank the fourth among female malignant tumors [1]. The incidence and mortality of cervical cancer are increasing at a younger age, posing a serious threat to women's health and life safety. In addition, cervical cancer is the second most common cancer in women in developing countries and 85% of cervical cancer deaths occur in developing countries [2], [3]. The recurrence rate of patients with stage I B-II A cervical cancer by Federation International of Gynecology and Obstetrics (FIGO) was 11%−22%, and that of patients with stage II B-IV cervical cancer by FIGO was 28%−64% [4]. The majority of cervical cancer is squamous cell carcinoma (CESC), accounting for more than 80%, while adenocarcinoma only accounts for 5%−10% [4], [5], [6]. Traditional cervical cancer treatment consists mostly of surgery, chemotherapy, and radiotherapy. A large number of studies have been devoted to exploring more effective and specific therapeutic methods and targeted therapeutic drugs for cervical cancer, so as to improve the therapeutic effect and quality of life of patients with cervical cancer. Therefore, cancer stem cells (CSCs) in cervical cancer are considered a potential therapeutic target [5], [6], [7].

CSCs are self-renewing cells that can generate heterogeneous tumor cells. They are the main cause of tumor heterogeneity and play an important role in tumorigenesis, metastasis, relapse, epithelial mesenchymal transformation (EMT), the resistance of chemotherapy and radiotherapy in cervical cancer, and have been considered as a new target for cancer treatment [8], [9]. In cervical cancer, CSCs is one of the key factors affecting the prognosis of patients with self-renewal potential, tumorigenicity, resistance to chemotherapy and radiotherapy. Targeted therapy for CSCs can prevent resistance to conventional therapy and limit tumor metastasis and recurrence. Apigenin, doxycycline and molecular iodine are effective for CSCs of cervical cancer, but the development of specific drugs or molecules for CSCs of cervical cancer is very limited, and there is a lack of relevant research reports on targeted therapy for CSCs of cervical cancer. Salinomycin nanoparticles can efficiently eradicate CSCs in cervical cancer, but its poor bioavailability and serious side effects limit its clinical application. By concurrently inhibiting CSCs and non-CSCs, Sal-Doc-loaded gelatinase-stimuli nanoparticles might be a promising method to improve antitumor effectiveness and lessen adverse effects [10]. Because there are no universal biomarkers for specifically identifying CSCs, a variety of cell surface and functional markers need to be used in order to identify CSCs in a specific tumor. There are several recognized CSCs markers in cervical cancer, such as CD133, ABCG2, OCT4, SOX2, ALDH1 and CD44 [11], [12], [13].

Ubiquitin carboxy-terminal hydrolase (UCHs) family have four members: UCHL1, UCHL3, UCHL37, and BRCA1-associated protein-1 (BAP1), which have a conserved catalytic domain (UCH-domain) consisting of about 230 amino acids [14], [15]. UCHL1 is a protein composed of 223 amino acids encoded by 9 exons. UCHL1 has the activity of denitrifying enzyme (DUB), which can catalyze the hydrolysis of ubiquitin (Ub) C-terminal ester and amide to produce monomer Ub. In addition, it also has the activity of E3 ubiquitin protein ligase and the role of stabilizing Ub monomer in vivo. UCHL1 is mainly found in neurons and neuroendocrine cells of the brain, and is associated with cell differentiation, proliferation, transcriptional regulation and many other biological processes [16]. UCHL1, as a marker of neurodegenerative diseases specifically expressed in the brain and testis, is also associated with the occurrence of tumors. Amyloid beta protein accumulation promotes target protein oxidation in patients with Alzheimer's disease. UCHL1 is also a substrate of oxidative stress response. After oxidation, UCHL1 protein loses its biological function, resulting in the failure of the target protein to separate from ubiquitin molecules in the UPS process, which leads to the imbalance of neurone ubiquitination/deubiquitination mechanism, the accumulation of amyloid beta and other proteins, and finally the degeneration of neurons [17]. At present, the main inhibitors against DUBs are small molecule inhibitors, but no inhibitors have entered the clinical stage. LDN-57444 has been widely used to inhibit the deubiquitination activity of UCHL1, but it is off-target toxic and chemically unstable, with limited binding to UCHL1. It has been reported that only GSK13S caused complete inhibition of UCHL1 after treatment of glioblastoma U-87MG cells with LDN-57444, GK13S, and GK16S for 24 h. MT16–001 is a covalent inhibitor of UCHL1 and has good selectivity to UCHL1, but its selection characteristics have not been determined. IMP-1710, the potent and selective inhibitor of UCHL1, blocked pro-fibrotic responses in a cell model of idiopathic pulmonary fibrosis [18], [19].

A lot of evidence suggests that UCHL1 promotes or inhibits cancer, but the role of UCHL1 in cancer is still controversial and the specific mechanism needs to be further explored. Many studies have shown that UCHL1 highly expressed in lung cancer, breast cancer, lymphoma and colorectal cancer, acting as an oncogene [18], [19], [20], [21], [22]. In breast cancer, high expression of UCHL1 causes EGFR deubiquitination and overactivation of MAPK signal, thus down-regulating ER expression and gene transcription [23]. Targeting UCHL1 can promote the degradation of EGFR protein and enhance the sensitivity of tumor cells to anti-estrogen therapy. On the contrary, certain research have revealed that due to promoter methylation, silencing or decreasing UCHL1 expression leaded to the progression of UCHL1 in various types of cancer, including pancreatic neuroendocrine tumors, nasopharyngeal carcinoma, hepatocellular carcinoma and other digestive tumors, and renal cell carcinoma [24], [25], [26], [27]. However, the role of UCHL1 remains unclear in cervical cancer.

In our study, we have found that UCHL1 is a prognostic factor and the survival rate of patients with high UCHL1 expression was significantly lower than that of patients with low UCHL1 expression in CESC. In addition, a series of in vitro and in vivo experiments further confirmed that UCHL1 promotes cancer stemness, proliferation, migration and invasion of CESC, which suggested that UCHL1 may be a novel therapeutic strategy for CESC treatment.

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